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Background: Edaravone was approved as a new treatment for amyotrophic lateral sclerosis (ALS), although there are different opinions on its effectiveness. Magnetic resonance (MRI) measures appear promising as diagnostic and prognostic indicators of disease. However, published studies on MRI using to monitor treatment efficacy in ALS are lacking., Purpose: The objective of this study was to investigate changes in brain MRI measures in patients treated with edaravone., Methods: Thirteen ALS patients assuming edaravone (ALS-EDA) underwent MRI at baseline (T0) and after 6 months (T6) to measure cortical thickness (CT) and fractional anisotropy (FA) of white matter (WM) tracts. MRI data of ALS-EDA were compared at T0 with those of 12 control subjects (CS), and at T6 with those of 11 ALS patients assuming only riluzole (ALS-RIL), extracted from our ALS cohort using a propensity-score-matching. A longitudinal MRI analysis was performed in ALS-EDA between T6 and T0., Results: At T0, ALS-EDA showed a cortical widespread thinning in both hemispheres, particularly in the bilateral precentral gyrus, and a reduction of FA in bilateral corticospinal tracts, in comparison to CS. Thinning in bilateral precentral cortex and significant widespread reduction of FA in several WM tracts were observed in ALS-EDA at T6 compared to T0. At T6, no significant differences in MRI measures of ALS-EDA versus ALS-RIL were found., Conclusions: Patients treated with edaravone showed progression of damage in the motor cortex and several WM tracts, at a six-month follow-up. Moreover, this study showed no evidence of a difference between edaravone and riluzole., (© 2021. The Author(s).)

Previous studies have reported an association between anti-tumor necrosis factor alpha (anti-TNFα) treatment and central nervous system (CNS) events. We described eight patients presenting with demyelinating CNS events while on treatment with anti-TNFα for autoimmune diseases and followed up for a medium period of 4 years. Four patients presented with isolated demyelinating events, three patients fulfilled the criteria for multiple sclerosis (MS), and one patient showed worsening of pre-existing MS after anti-TNF therapy initiation. All patients except one, showed a good medium-term prognosis. Our observation supports an association between anti-TNFα treatment and demyelinating events and suggests that a prompt discontinuation of the drug may lead to a favorable demyelinating disease outcome., (© 2021. Springer-Verlag GmbH, DE part of Springer Nature.)

Background: In amyotrophic lateral sclerosis (ALS), the involvement of lower motor neuron is well defined by electromyography, whereas a reliable marker of upper motor neuron (UMN) damage still lacks. Aim of the study was to estimate the role of transcranial magnetic stimulation (TMS)-induced motor-evoked potentials (MEPs) as marker of subclinical UMN involvement., Methods: Clinical evidence of UMN damage was prospectively compared to MEPs in 176 ALS patients diagnosed between 2011 and 2014, and classified according to existing diagnostic criteria. Finally, we evaluated the appearance of clinical UMN signs and the level of diagnostic certainty in ALS after 1 year of follow-up., Results: At presentation, abnormal MEPs were found in 80% of patients with clinical evidence of UMN damage and in 72% of patients without clinical involvement of UMN. Among these latter, 61% showed appearance of UMN clinical signs after 1 year. Approximately 70% of patients with clinical lower motor neuron (LMN) phenotype showed MEP abnormalities, while they were considered not classifiable ALS according to Airlie house or Awaji criteria. Furthermore, abnormal MEPs in absence of clinical UMN signs at baseline were found in 80% of spinal ALS that after 1-year developed UMN signs at limbs, compared to 50% of bulbar ALS., Conclusions: TMS is a reliable marker of subclinical UMN damage particularly among LMN phenotype and ensure an early ALS diagnosis in ~ 70% of such cases.

Objectives: The aim of the study is to analyze the ALS disease progression and respiratory function of Italian patients treated with edaravone (EVN), as well as the adherence to, and the effects of, the therapy., Methods: We performed an observational study of patients treated with EVN from May 2017 to May 2019, in 39 Italian ALS Centers. Taking into account ALS patients with at least 12 months of EVN treatment, we compared the decline of ALSFRS-R and FVC with a group of matched historical controls from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, using both descriptive and survival analysis approaches., Results: A total of 331 ALS Italian patients treated with EVN and 290 matched historical controls were recruited in this study. No significant differences on disease progression or respiratory function were found comparing the two cohorts in both descriptive and survival analyses. The EVN treatment was overall well tolerated., Conclusions: The study showed that EVN treatment was well tolerated. No significant differences were reported in ALS patients treated and not treated with EVN, in terms of both disease progression and respiratory function. These findings prove that further studies are required to better clarify whether EVN could be considered an effective treatment for ALS disease.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that still lacks reliable diagnostic biomarkers. This study aims to evaluate the diagnostic and prognostic potential of CSF total Tau (t-Tau), phospho-Tau (p-Tau) and p-Tau/t-Tau ratio in ALS patients using CSF neurofilament light (NFL) as the reference biomarker., Methods: Eighty-five incident ALS, 30 ALS-mimicking (AM) diseases and 51 other non-neurodegenerative diseases (ONND) were included in the study., Results: ALS patients had higher levels of CSF t-Tau and lower p-Tau/t-Tau ratio than AM (p = 0.005 and p = 0.006) and ONND (p < 0.001). CSF t-Tau levels discriminated ALS from AM with a sensitivity of 69% and specificity of 60%, and from ONND with a sensitivity of 88% and specificity of 51%. These values were lower than the accuracy of CSF NFL in ALS (sensitivity 86% and specificity 87% in distinguishing ALS from AM and sensitivity 83% and specificity 75% from ONND); CSF t-Tau correlated with progression rate and SNIP. CSF p-Tau did not show relation with any ALS clinical features. CSF NFL significantly correlated with all considered clinical parameters. High levels of CSF t-Tau and NFL were related to poor survival., Conclusion: CSF t-Tau showed no reliable diagnostic significance but the relation between the high levels of CSF t-Tau and short survival suggests the potential prognostic role of this biomarker in ALS. However, CSF NFL was confirmed to be the most reliable and efficient tool for diagnosis and prediction of clinical progression and survival in ALS patients.

The aim of this study is to investigate the frequency and the clinical correlations of pseudobulbar affect (PBA) in a population-based incident cohort of ALS patients. Incident ALS cases, diagnosed in 2011 and 2012, according to El Escorial criteria were enrolled from a prospective population-based registry in Apulia, Southern Italy. Neurological status was assessed using a standard neurological examination and the revised ALS Functional Rating Scale (ALSFRSr). The Center for Neurologic Study-Lability Scale (CNS-LS), a self-administered questionnaire, was used to evaluate the presence and severity of PBA. Total scores range from 7 to 35. A score ≥13 was used to identify the presence of PBA. One-hundred thirty-two sporadic incident ALS cases were enrolled. Median disease duration was 20 months (range 2-143), median onset-diagnosis interval (ODI) 12 months (range 2-131), median ALSFRSr at baseline 36/48 (range 2-47) and median ALSFRSr bulbar sub-score 10/12 (range 0-12). Neurological examination revealed presence of PBA in 34/132 patients (26%). Pathological CNS-LS score was found in 45/132 patients (34%). Median total CNS-LS score was 9/35 (range 7-29). The subgroup with pathological CNS-LS was characterized by a short disease duration from symptom onset, ODI, time to diffusion to a second region, time to generalization and ALSFRSr bulbar sub-score, bulbar onset, "definite" diagnostic category, bulbar upper motor-neuron involvement and presence of PBA at neurological examination. In population-based setting, one-third of ALS patients present PBA at diagnosis. The presence of PBA is associated with bulbar UMN involvement and markers of a more severe phenotype.

Forced vital capacity (FVC) shows limitations in detecting respiratory failure in the early phase of amyotrophic lateral sclerosis (ALS). In fact, mild-to-moderate respiratory muscle weakness may be present even when FVC is normal, and ALS patients with bulbar involvement might not be able to perform correctly the spirometry test. Sniff nasal inspiratory pressure (SNIP) is correlated with transdiaphragmatic strength. We evaluated SNIP at baseline as a prognostic factor of tracheostomy or death in patients with ALS. In a multidisciplinary tertiary care center for motorneuron disease, we enrolled 100 patients with ALS diagnosed with El Escorial criteria in the period between January 2006 and December 2010. Main outcome measures were tracheostomy or death. RECursive Partitioning and AMalgamation (RECPAM) analysis was also used to identify subgroups at different risks for the tracheostomy or death. Twenty-nine patients with ALS reached the outcome (12 died and 17 had tracheostomy). Using a multivariate model SNIP correctly classified the risk of the composite event within 1 year of follow-up with a continuous Net Reclassification Improvement cNRI of 0.58 (p = 0.03). Sex, Amyotrophic Lateral Sclerosis Functional Rating Scale revisited, site of onset, and FVC did not improve the classification of prognostic classes. SNIP ≤18 cmH2O identified the RECPAM class with the highest risk (Class 1, hazard ratio = 9.85, 95 % confidence interval: 2.67-36.29, p < 0.001). SNIP measured at baseline identified patients with ALS with initial respiratory failure. Finally, using only ALS patients with spinal onset of the disease, our findings were mostly overlapping with those reported in the models including the whole sample. At baseline, SNIP appeared to be the best predictor of death or tracheostomy within 1 year of follow-up. The measurement of SNIP in the early phase of the disease may contribute to identify patients with high risk of mortality or intubation. SNIP may also provide an additional tool for baseline stratification of patients with ALS in clinical trials.

Urate is a natural antioxidant, and high serum urate levels could be protective against the development of amyotrophic lateral sclerosis (ALS). To determine if serum urate concentrations were lower in ALS patients than in healthy controls, we compared serum urate levels in 132 ALS patients and 337 age/sex-matched controls. Median urate levels were lower in ALS patients compared to controls (4.2mgl/dL [range:1.4-8.2], vs. 4.7 [1.7-13.1]; p = 0.04). In univariate analysis, high urate levels were less likely to be associated with ALS (odds ratio [OR]: 0.53; 95% CI: 0.29-0.97; p = 0.04), but after adjusting for age, sex and kidney function, the association was not statistically significant (OR: 0.63; 95% CI: 0.32-1.24; p = 0.18). Urate levels were lower in bulbar-onset ALS (3.9 mg/dL), compared to limb-onset ALS (4.3; p = 0.001), and in cases with longer disease duration compared to controls (4.1 mg/dL, vs. 4.7; p = 0.01). In this cross-sectional study, lower levels of serum urate were evident in ALS cases with bulbar-onset and longer disease duration, but were likely to be related to the malnutrition induced by ALS.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motorneurons, for which there is no effective cure. Because of the multifactorial nature of impairment and disablity in ALS, multidisciplinary clinics (MDC) have been recently introduced in the management of ALS patients; their effects on survival remain, however, largely debated., Objective: To compare survival of ALS patients who received their care at MDC with that of patients followed by general neurology clinics., Methods: Source of the study was a prospective population-based registry of ALS established in Puglia, Southern Italy, in 1997. We examined survival of 126 out of 130 incident ALS cases that were diagnosed during the period 1998-99., Results: 84 patients (67%) were enrolled and followed by MDC and the remaining 42 (33%) by general neurological clinics. No difference in median survival time from the diagnosis was observed between patients followed by ALS multidisciplinary (17.6 months) and general clinics (18 months). No beneficial effect was present among bulbar onset ALS (11.7 versus 23 months). In multivariate analysis management by ALS MDC was associated with only a 10% increase in survival probability at 12 months (HR: 0.91; 95%CI: 0.44-1.89; p = 0.9)., Conclusions: In this population-based series, we found that in Southern Italy management of ALS by multidisciplinary clinics does not improve survival, regardless of site of symptoms onset.

Single-voxel proton magnetic resonance spectroscopy (1H-MRS), localised to the basal ganglia, was used to determine changes in metabolite levels in idiopathic spasmodic torticollis (IST). We examined nine patients and 13 healthy subjects. The mean values (+/- SD) of peak area ratios were: IST: N-acetyl-aspartate (NAA)/choline-containing compounds (Cho) 1.79 +/- 0.39, NAA/creatine and phosphocreatine compounds (Cr) 1.61 +/- 0.38, Cho/Cr 0.91 +/- 0.19; controls: NAA/Cho 2.07 +/- 0.35, NAA/ Cr 1.82 +/- 0.31, Cho/Cr 0.89 +/- 0.12. Statistical analysis showed that NAA/Cho and NAA/Cr were significantly lower in patients than in controls (P = 0.0304 and 0.0431, respectively). These results indicate a reduction in NAA, and suggest striatal involvement in the pathogenesis IST.

Proton magnetic resonance spectroscopy has proved to be useful for monitoring a number of metabolites in cerebral infarction. Combined magnetic resonance imaging and spectroscopy investigations were carried out in 14 patients with a recent ischaemic stroke (< 1 week); follow-up examinations were performed from day 28 to day 252 after stroke. The aim of this study was to assess the correlation between the changes of N-acetyl-aspartate, choline, creatine-phosphocreatine, lactate and clinical evolution measured by the Scandinavian Neurological Scale (SNS). Initially the lactate magnetic resonance signal was present in all patients and the other metabolite contents were significantly reduced (P < 0.001; unpaired t-test) as compared with those on the contralateral side. Spearman's rank correlation test showed a positive correlation between the initial reduction of N-acetyl-aspartate content and the SNS (P < 0.05), and between the final N-acetyl-aspartate content and the SNS (P < 0.001). Our results suggest that serial examination in stroke patients may provide further prognostic information and encourage controlled clinical studies.

Isoelectric focusing of CSF and serum IgG followed by crossed immuno isoelectric focusing and direct immunofixation as well as quantitative assay of IgG and albumin were performed in 64 clinically definite multiple sclerosis patients. Intrathecal IgG synthesis was calculated according to the CSF IgG index and de novo CNS IgGsyn. Isoelectric focusing showed abnormal IgG fractions i CSF indicating increased intrathecal synthesis of oligoclonal IgG in 99% of patients. Only 62% and 70% of multiple sclerosis patients showed values of CSF IgG indices and de novo CNS IgGsyn higher than in controls. Increased intrathecal IgG synthesis was indicated more frequently by de novo CNS IgGsyn in patients with a normal CSF IgG index than by the CSF IgG index in patients with normal de novo CNS IgGsyn. All patients with blood CSF barrier damage had increased de novo CNS IgGsyn, but only 40% had an increased CSF IgG index. Isoelectric focusing seemed to be a more sensitive method to detect an increased intrathecal oligoclonal IgG synthesis than quantitative methods. Identification of abnormal IgG fractions can be performed easily and with more reproducible results by direct immunofixation than by crossed immuno isoelectric focusing. The formula for de novo CNS IgGsyn seemed more sensitive and less influenced by blood-CSF barrier damage than the CSF IgG index to detect increased intrathecal IgG synthesis in multiple sclerosis patients. No correlation was found between the CSF IgG pattern or amounts and age, duration, clinical course or therapy of the disease.

Ten children affected by acute lymphoblastic leukaemia without CNS involvement were treated with a CNS prophylaxis protocol. Intrathecal methotrexate and CNS irradiation (60Co) administered at different times both induced an increase in blood-CSF barrier permeability to serum proteins (albumin, IgG, alpha 2 macroglobulin). The relationship between permeability coefficients of proteins was analysed by theoretical porous or vesicular blood-CSF barrier models. The analysis indicated that both therapeutic procedures affect endothelial pinocytosis. An increase in radius of pinocytotic vesicles from 400 to 1500 A seemed the most relevant change. The damage of endothelial barrier permselectivity could be involved in acute and late delayed toxic effects of intrathecal methotrexate and of CNS irradiation.

Isoelectric focusing and quantitative estimation of serum and CSF IgG were performed in 85 patients with idiopathic polyneuropathy (IP), subdivided according to the clinical course (acute, subacute, recurrent, chronic). Acute IP very frequently had an increase of oligoclonal and/or polyclonal serum IgG during the progressive phase and blood-CSF barrier damage accompanied by polyclonal IgG intrathecal synthesis during the stationary phase. Polyclonal IgG intrathecal synthesis was also present in several not acute IP and seemed to forecast unfavorable course. Oligoclonal IgG synthesis occurs very rarely within CSF but is a frequent finding in serum of patients with IP. Abnormalities of the IgG serum pattern are neither specific for any clinical course of IP nor of prognostic value. The possible significance of such findings is discussed.